Using Gene Editing Approaches to Fine-Tune the Immune System
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AuthorPavlovic, Kristina; Tristán Manzano, María; Maldonado Pérez, Noelia; Cortijo Gutierrez, Marina; Sánchez Hernández, Sabina; Justicia Lirio, Pedro; Martín Molina, Francisco; Benabdellah, Karim
Frontiers Media SA
ImmunotherapyCARsGene editingGraft-vs-host diseaseBase editors
Pavlovic K, Tristán-Manzano M, Maldonado-Pérez N, Cortijo-Gutierrez M, Sánchez-Hernández S, Justicia-Lirio P, Carmona MD, Herrera C, Martin F and Benabdellah K (2020) Using Gene Editing Approaches to Fine-Tune the Immune System. Front. Immunol. 11:570672. [doi: 10.3389/fimmu.2020.570672]
SponsorshipSpanish ISCIII Health Research Fund; European Union (EU) PI12/01097 PI15/02015 PI18/00337 PI18/00330; CECEyU and CSyF councils of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) 2016000073391-TRA 2016000073332-TRA PI-57069 PAIDI-Bio326 PI-0014-2016; Nicolas Monardes regional Ministry of Health 0006/2018; Spanish Government FPU16/05467 FPU17/02268; Industrial Doctorate Plan MCI DIN2018-010180; SMSI PEJ-2018-001760-A; LentiStem Biotech
Genome editing technologies not only provide unprecedented opportunities to study basic cellular system functionality but also improve the outcomes of several clinical applications. In this review, we analyze various gene editing techniques used to finetune immune systems from a basic research and clinical perspective. We discuss recent advances in the development of programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We also discuss the use of programmable nucleases and their derivative reagents such as base editing tools to engineer immune cells via gene disruption, insertion, and rewriting of T cells and other immune components, such natural killers (NKs) and hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric antigen receptors (CARs), we describe how different gene editing tools enable healthy donor cells to be used in CAR T therapy instead of autologous cells without risking graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs and instant treatment availability for patients. We pay particular attention to the delivery of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral damage and increases therapeutic effectiveness. Finally, we review creative innovations, including immune system repurposing, that facilitate safe and efficient genome surgery within the framework of clinical cancer immunotherapies.